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Studies Confirm COVID-19 mRNA Vaccines Safe, Effective for Pregnant Women

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Credit: GettyImages/bogdankosanovic

Clinical trials have shown that COVID-19 vaccines are remarkably effective in protecting those age 12 and up against infection by the coronavirus SARS-CoV-2. The expectation was that they would work just as well to protect pregnant women. But because pregnant women were excluded from the initial clinical trials, hard data on their safety and efficacy in this important group has been limited.

So, I’m pleased to report results from two new studies showing that the two COVID-19 mRNA vaccines now available in the United States appear to be completely safe for pregnant women. The women had good responses to the vaccines, producing needed levels of neutralizing antibodies and immune cells known as memory T cells, which may offer more lasting protection. The research also indicates that the vaccines might offer protection to infants born to vaccinated mothers.

In one study, published in JAMA [1], an NIH-supported team led by Dan Barouch, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, wanted to learn whether vaccines would protect mother and baby. To find out, they enrolled 103 women, aged 18 to 45, who chose to get either the Pfizer/BioNTech or Moderna mRNA vaccines from December 2020 through March 2021.

The sample included 30 pregnant women,16 women who were breastfeeding, and 57 women who were neither pregnant nor breastfeeding. Pregnant women in the study got their first dose of vaccine during any trimester, although most got their shots in the second or third trimester. Overall, the vaccine was well tolerated, although some women in each group developed a transient fever after the second vaccine dose, a common side effect in all groups that have been studied.

After vaccination, women in all groups produced antibodies against SARS-CoV-2. Importantly, those antibodies neutralized SARS-CoV-2 variants of concern. The researchers also found those antibodies in infant cord blood and breast milk, suggesting that they were passed on to afford some protection to infants early in life.

The other NIH-supported study, published in the journal Obstetrics & Gynecology, was conducted by a team led by Jeffery Goldstein, Northwestern’s Feinberg School of Medicine, Chicago [2]. To explore any possible safety concerns for pregnant women, the team took a first look for any negative effects of vaccination on the placenta, the vital organ that sustains the fetus during gestation.

The researchers detected no signs that the vaccines led to any unexpected damage to the placenta in this study, which included 84 women who received COVID-19 mRNA vaccines during pregnancy, most in the third trimester. As in the other study, the team found that vaccinated pregnant women showed a robust response to the vaccine, producing needed levels of neutralizing antibodies.

Overall, both studies show that COVID-19 mRNA vaccines are safe and effective in pregnancy, with the potential to benefit both mother and baby. Pregnant women also are more likely than women who aren’t pregnant to become severely ill should they become infected with this devastating coronavirus [3]. While pregnant women are urged to consult with their obstetrician about vaccination, growing evidence suggests that the best way for women during pregnancy or while breastfeeding to protect themselves and their families against COVID-19 is to roll up their sleeves and get either one of the mRNA vaccines now authorized for emergency use.

References:

[1] Immunogenicity of COVID-19 mRNA vaccines in pregnant and lactating women. Collier AY, McMahan K, Yu J, Tostanoski LH, Aguayo R, Ansel J, Chandrashekar A, Patel S, Apraku Bondzie E, Sellers D, Barrett J, Sanborn O, Wan H, Chang A, Anioke T, Nkolola J, Bradshaw C, Jacob-Dolan C, Feldman J, Gebre M, Borducchi EN, Liu J, Schmidt AG, Suscovich T, Linde C, Alter G, Hacker MR, Barouch DH. JAMA. 2021 May 13.

[2] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in pregnancy: Measures of immunity and placental histopathology. Shanes ED, Otero S, Mithal LB, Mupanomunda CA, Miller ES, Goldstein JA. Obstet Gynecol. 2021 May 11.

[3] COVID-19 vaccines while pregnant or breastfeeding. Centers for Disease Control and Prevention.

Links:

COVID-19 Research (NIH)

Barouch Laboratory (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston)

Jeffery Goldstein (Northwestern University Feinberg School of Medicine, Chicago)

NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institute of Child Health and Human Development; National Center for Advancing Translational Sciences; National Institute of Biomedical Imaging and Bioengineering


Caught on Camera: Neutralizing Antibodies Interacting with SARS-CoV-2

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Caption: Illustration showing the binding regions for the four classes of SARS-CoV-2 neutralizing antibodies. They bind to a part of the virus’s spike protein called the receptor binding domain (gray). Credit: Christopher Barnes, California Institute of Technology, Pasadena

As this long year enters its final month, there is good reason to look ahead to 2021 with optimism that the COVID-19 pandemic will finally be contained. The Food and Drug Administration is now reviewing the clinical trial data of the Pfizer and Moderna vaccines to ensure their safety and efficacy. If all goes well, emergency use authorization could come very soon, allowing immunizations to begin.

Work also continues on developing better therapeutics against SARS-CoV-2, the novel coronavirus that causes COVID-19. Though we’ve learned a great deal about this coronavirus in a short time, structural biologists continue to produce more detailed images that reveal more precisely where and how to target SARS-CoV-2. This research often involves neutralizing antibodies that circulate in the blood of most people who’ve recovered from COVID-19. The study of such antibodies and how they interact with SARS-CoV-2 offers critical biological clues into how to treat and prevent COVID-19.

A recent study in the journal Nature brings more progress, providing the most in-depth analysis yet of how human neutralizing antibodies physically grip SARS-CoV-2 to block it from binding to our cells [1]. To conduct this analysis, a team of NIH-supported structural biologists, led by postdoc Christopher Barnes and Pamela Björkman, California Institute of Technology, Pasadena, used the power of cryo-electron microscopy (cryo-EM) to capture complex molecular interactions at near-atomic scale.

People infected with SARS-CoV-2 (or any foreign substance, for that matter) generate thousands of different versions of attack antibodies. Some of these antibodies are very good at sticking to the coronavirus, while others attach only loosely. Barnes used cryo-EM to capture highly intricate pictures of eight different human neutralizing antibodies bound tightly to SARS-CoV-2. Each of these antibodies, which had been isolated from patients a few weeks after they developed symptoms of COVID-19, had been shown in lab tests to be highly effective at blocking infection.

The researchers mapped all physical interactions between several human neutralizing antibodies and SARS-CoV-2’s spike protein that stud its surface. The virus uses these spiky extensions to infect a human cell by grabbing on to the angiotensin-converting enzyme 2 (ACE2) receptor. The molecular encounter between the coronavirus and ACE2 takes place via one or more of a trio of three protein domains, called receptor-binding domains (RBDs), that jut out from its spikes. RBDs flap up and down in the fluid surrounding cells, “reaching up” to touch and enter, or “laying down” to hide from an infected person’s antibodies and immune cells. Only an “up” RBD can attach to ACE2 and get into a cell.

Taken together with other structural information known about SARS-CoV-2, Barnes’ cryo-EM snapshots revealed four different types of shapes, or classes, of antibody-spike combinations. These high-resolution molecular views show that human neutralizing antibodies interact in many different ways with SARS-CoV-2: blocking access to either one or more RBDs in their “up” or “down” positions.

These results tell us a number of things, including underscoring why strategies that combine multiple types of antibodies in an “antibody cocktail” might likely offer broader protection against infection than using just a single type of antibody. Indeed, that approach is currently being tested in patients with COVID-19.

The findings also provide a molecular guide for custom-designing synthetic antibodies in the lab to foil SARS-CoV-2. As one example, Barnes and his team observed that one antibody completely locked all three RBDs into closed (“down”) positions. As you might imagine, scientists might want to copy that antibody type when designing an antibody-based drug or vaccine.

It is tragic that hundreds of thousands of people have died from this terrible new disease. Yet the immune system helps most to recover. Learning as much as we possibly can from those individuals who’ve been infected and returned to health should help us understand how to heal others who develop COVID-19, as well as inform precision design of additional vaccines that are molecularly targeted to this new foe.

While we look forward to the arrival of COVID-19 vaccines and their broad distribution in 2021, each of us needs to remember to practice the three W’s: Wear a mask. Watch your distance (stay 6 feet apart). Wash your hands often. In parallel with everyone adopting these critical public health measures, the scientific community is working harder than ever to meet this moment, doing everything possible to develop safe and effective ways of treating and preventing COVID-19.

Reference:

[1] SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Barnes CO, Jette CA, Abernathy ME, et al. Nature. 2020 Oct 12. [Epub ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Freezing a Moment in Time: Snapshots of Cryo-EM Research (National Institute of General Medical Sciences/NIH)

Björkman Lab (California Institute of Technology, Pasadena)

NIH Support: National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases


Researchers Publish Encouraging Early Data on COVID-19 Vaccine

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Diagram of how mRNA vaccine works
Credit: NIH

People all around the globe are anxiously awaiting development of a safe, effective vaccine to protect against the deadly threat of coronavirus disease 2019 (COVID-19). Evidence is growing that biomedical research is on track to provide such help, and to do so in record time.

Just two days ago, in a paper in the New England Journal of Medicine [1], researchers presented encouraging results from the vaccine that’s furthest along in U.S. human testing: an innovative approach from NIH’s Vaccine Research Center (VRC), in partnership with Moderna Inc., Cambridge, MA [1]. The centerpiece of this vaccine is a small, non-infectious snippet of messenger RNA (mRNA). Injecting this mRNA into muscle will spur a person’s own body to make a key viral protein, which, in turn, will encourage the production of protective antibodies against SARS-CoV-2—the novel coronavirus that causes COVID-19.

While it generally takes five to 10 years to develop a vaccine against a new infectious agent, we simply don’t have that time with a pandemic as devastating as COVID-19. Upon learning of the COVID-19 outbreak in China early this year, and seeing the genome sequence of SARS-CoV-2 appear on the internet, researchers with NIH’s National Institute of Allergy and Infectious Diseases (NIAID) carefully studied the viral instructions, focusing on the portion that codes for a spike protein that the virus uses to bind to and infect human cells.

Because of their experience with the original SARS virus back in the 2000s, they thought a similar approach to vaccine development would work and modified an existing design to reflect the different sequence of the SARS-CoV-2 spike protein. Literally within days, they had created a vaccine in the lab. They then went on to work with Moderna, a biotech firm that’s produced personalized cancer vaccines. All told, it took just 66 days from the time the genome sequence was made available in January to the start of the first-in-human study described in the new peer-reviewed paper.

In the NIH-supported phase 1 human clinical trial, researchers found the vaccine, called mRNA-1273, to be safe and generally well tolerated. Importantly, human volunteers also developed significant quantities of neutralizing antibodies that target the virus in the right place to block it from infecting their cells.

Conducted at Kaiser Permanente Washington Health Research Institute, Seattle; and Emory University School of Medicine, Atlanta, the trial led by Kaiser Permanente’s Lisa Jackson involved healthy adult volunteers. Each volunteer received two vaccinations in the upper arm at one of three doses, given approximately one month apart.

The volunteers will be tracked for a full year, allowing researchers to monitor their health and antibody production. However, the recently published paper provides interim data on the phase 1 trial’s first 45 participants, ages 18 to 55, for the first 57 days after their second vaccination. The data revealed:

• No volunteers suffered serious adverse events.

• Optimal dose to elicit high levels of neutralizing antibody activity, while also protecting patient safety, appears to be 100 micrograms. Doses administered in the phase 1 trial were either 25, 100, or 250 micrograms.

• More than half of the volunteers reported fatigue, headache, chills, muscle aches, or pain at the injection site. Those symptoms were most common after the second vaccination and in volunteers who received the highest vaccine dose. That dose will not be used in larger trials.

• Two doses of 100 micrograms of the vaccine prompted a robust immune response, which was last measured 43 days after the second dose. These responses were actually above the average levels seen in blood samples from people who had recovered from COVID-19.

These encouraging results are being used to inform the next rounds of human testing of the mRNA-1273 vaccine. A phase 2 clinical trial is already well on its way to recruiting 600 healthy adults.This study will continue to profile the vaccine’s safety, as well as its ability to trigger an immune response.

Meanwhile, later this month, a phase 3 clinical trial will begin enrolling 30,000 volunteers, with particular focus on recruitment in regions and populations that have been particularly hard hit by the virus.

The design of that trial, referred to as a “master protocol,” had major contributions from the Accelerating COVID-19 Therapeutic Interventions and Vaccine (ACTIV) initiative, a remarkable public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies. Now, a coordinated effort across the U.S. government, called Operation Warp Speed, is supporting rapid conduct of these clinical trials and making sure that millions of doses of any successful vaccine will be ready if the vaccine proves save and effective.

Results of this first phase 3 trial are expected in a few months. If you are interested in volunteering for these or other prevention trials, please check out NIH’s new COVID-19 clinical trials network.

There’s still a lot of work that remains to be done, and anything can happen en route to the finish line. But by pulling together, and leaning on the very best science, I am confident that we will be able rise to the challenge of ending this pandemic that has devastated so many lives.

Reference:

[1] A SARS-CoV-2 mRNA Vaccine—Preliminary Report. Jackson LA, Anderson EJ, Rouphael NG, Ledgerwood JE, Graham BS, Beigel JH, et al. NEJM. 2020 July 14. [Publication ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)

Moderna, Inc. (Cambridge, MA)

Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) (ClinicalTrials.gov)

NIH Launches Clinical Trials Network to Test COVID-19 Vaccines and Other Prevention Tools,” NIAID News Release, NIH, July 8, 2020.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

Explaining Operation Warp Speed (U.S. Department of Health and Human Services, Washington, DC)

NIH Support: National Institute of Allergy and Infectious Diseases


Study in Primates Finds Acquired Immunity Prevents COVID-19 Reinfections

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SARS-CoV-2 and Antibodies

There have been rare reports of people recovering from infection with SARS-CoV-2, the novel coronavirus that causes COVID-19, only to test positive a second time. Such results might be explained by reports that the virus can linger in our systems. Yet some important questions remain: Is it possible that people could beat this virus only to get reinfected a short time later? How long does immunity last after infection? And what can we expect about the duration of protection from a vaccine?

A recent study of rhesus macaques, which are among our close primate relatives, offers relevant insights into the first question. In a paper published in the journal Science, researchers found that after macaques recover from mild SARS-CoV-2 infection, they are protected from reinfection—at least for a while.

In work conducted in the lab of Chuan Qin, Peking Union Medical College, Beijing, China, six macaques were exposed to SARS-CoV-2. Following infection, the animals developed mild-to-moderate illness, including pneumonia and evidence of active infection in their respiratory and gastrointestinal tracts. Twenty-eight days later, when the macaques had cleared the infection and started recovering, four animals were re-exposed to the same strain of SARS-CoV-2. The other two served as controls, with researchers monitoring their continued recovery.

Qin’s team noted that after the second SARS-CoV-2 exposure, the four macaques developed a transient fever that had not been seen after their first infection. No other signs of reinfection were observed or detected in chest X-rays, and the animals tested negative for active virus over a two-week period.

While more study is needed to understand details of the immune responses, researchers did detect a reassuring appearance of antibodies specific to the SARS-CoV-2 spike protein in the macaques over the course of the first infection. The spike protein is what the virus uses to attach to macaque and human cells before infecting them.

Of interest, levels of those neutralizing antibodies were even higher two weeks after the second viral challenge than they were two weeks after the initial exposure. However, researchers note that it remains unclear which factors specifically were responsible for the observed protection against reinfection, and apparently the first exposure was sufficient.

Since the second viral challenge took place just 28 days after the first infection, this study provides a rather limited window into broad landscape of SARS-CoV-2 infection and recovery. Consequently, it will be important to determine to what extent a first infection might afford protection over the course of months and even years. Also, because the macaques in this study developed only mild-to-moderate COVID-19, more research is needed to investigate what happens after recovery from more severe COVID-19.

Of course, macaques are not humans. Nevertheless, the findings lend hope that COVID-19 patients who develop acquired immunity may be at low risk for reinfection, at least in the short term. Additional studies are underway to track people who came down with COVID-19 in New York during March and April to see if any experience reinfection. By the end of this year, we should have better answers.

Reference:

[1] Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Deng W, Bao L, Liu J, et al. Science. 2020 Jul 2. [Published online ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

Qin Lab (Peking Union Medical College, Beijing, China)


Finding Antibodies that Neutralize SARS-CoV-2

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Neutralizing Antibodies
Caption: Model of three neutralizing antibodies (blue, purple and orange) bound to the spike protein, which allows SARS-CoV-2 attach to our cells. Credit: Christopher Barnes and Pamela Bjorkman, California Institute of Technology, Pasadena.

It’s now clear that nearly everyone who recovers from coronavirus disease 2019 (COVID-19) produces antibodies that specifically target SARS-CoV-2, the novel coronavirus that causes the infection. Yet many critical questions remain. A major one is: just how well do those particular antibodies neutralize the virus to fight off the infection and help someone recover from COVID-19? Fortunately, most people get better—but should the typical antibody response take the credit?

A new NIH-funded study of nearly 150 people who recovered from COVID-19 offers some essential insight. The study, published in the journal Nature, shows that most people, in fact, do produce antibodies that can effectively neutralize SARS-CoV-2. But there is a catch: 99 percent of the study’s participants didn’t make enough neutralizing antibodies to mount an ideal immune response.

The good news is that when researchers looked at individuals who mounted a strong immune response, they were able to identify three antibodies (depicted above) that were extremely effective at neutralizing SARS-CoV-2. By mass-producing copies of these antibodies as so-called monoclonal antibodies, the researchers can now better evaluate their potential as treatments to help people who don’t make strongly neutralizing antibodies, or not enough of them.

These findings come from a team led by Michel Nussenzweig, Paul Bieniasz, and Charles Rice at The Rockefeller University, New York, and Pamela Bjorkman at the California Institute of Technology, Pasadena. In the Nussenzweig lab, the team has spent years searching for broadly neutralizing antibodies against the human immunodeficiency virus (HIV). In response to the COVID-19 pandemic and its great urgency, Nussenzweig and team shifted their focus recently to look for promising antibodies against SARS-CoV-2.

Antibodies are blood proteins that the immune system makes to neutralize viruses or other foreign invaders. The immune system doesn’t make just one antibody to thwart an invader; it makes a whole family of antibodies. But not all antibodies in that family are created equal. They can vary widely in where they latch onto a virus like SARS-CoV-2, and that determines how effective each will be at blocking it from infecting human cells. That’s one reason why people respond differently to infections such as COVID-19.

In early April, Nussenzweig’s team began analyzing samples from volunteer survivors who visited The Rockefeller Hospital to donate plasma, which contains the antibodies. The volunteers had all recovered from mild-to-severe cases of COVID-19, showing their first signs of illness about 40 days prior to their first plasma collection.

Not surprisingly, all volunteers had produced antibodies in response to the virus. To test the strength of the antibodies, the researchers used a special assay that shows how effective each one is at blocking the virus from infecting human cells in lab dishes.

Overall, most of the plasma samples—118 of 149—showed at best poor to modest neutralizing activity. In about one-third of individuals, their plasma samples had below detectable levels of neutralizing activity. It’s possible those individuals just resolved the infection quickly, before more potent antibodies were produced.

More intriguing to the researchers were the results from two individuals that showed an unusually strong ability to neutralize SARS-CoV-2. Among these two “elite responders” and four other individuals, the researchers identified 40 different antibodies that could neutralize SARS-CoV-2. But again, not all antibodies are created equal. Three neutralized the virus even when present at extremely low levels, and they now will be studied further as possible monoclonal antibodies.

The team determined that those strongly neutralizing antibodies bind three distinct sites on the receptor-binding domain (RBD) of the coronavirus spike protein. This portion of the virus is important because it allows SARS-CoV-2 to bind and infect human cells. Importantly, when the researchers looked more closely at plasma samples with poor neutralizing ability, they found that they also contained those RBD-binding antibodies, just not in very large numbers.

These findings help not only to understand the immune response to COVID-19, they are also critical for vaccine design, revealing what a strong neutralizing antibody for SARS-CoV-2 should look like to help the immune system win. If a candidate vaccine can generate such strongly neutralizing antibodies, researchers will know that they are on the right track.

While this research showed that there’s a lot of variability in immune responses to SARS-CoV-2, it appears that most of us are inherently capable of producing antibodies to neutralize this devastating virus. That brings more reason for hope that the many vaccines now under study to elicit such neutralizing antibodies in sufficient numbers may afford us with much-needed immune protection.

Reference:

[1] Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Robbiani DF, Gaebler C, Muecksch F, et al. Nature. 2020 Jun 18. [Published online ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

Nussenzweig Lab (The Rockefeller University, New York)

Bjorkman Lab (California Institute of Technology, Pasadena)

NIH Support: National Institute of Allergy and Infectious Diseases


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